The dopamine neurons of the ventral tegmental area and substantia nigra pars compacta, located within the ventral mesencephalon, encode perhaps one of the most important signals for reinforcement learning in the brain - reward prediction error. This signal is encoded by the firing pattern of dopamine neurons, which controls the release of dopamine at target regions. Specifically, transient, impulse- dependent release of dopamine, driven by bursts of action potentials, is critical for natural processing in the brain. Just as critical, pauses in dopamine cell activity have opposite psychological meaning for reward information coding and are thought to signal the absence of an expected reward. It is likely the essential nature of this signal that connects disruptions of DA function to many of the symptoms of a wide range of psychiatric diseases, and in the extreme case of the degeneration of these cells, to Parkinson's disease, including many of its cognitive aspects. Identification of the input pathways responsible for bursts and pauses is a key step in understanding the mechanism of reinforcement learning, but has so far proven elusive, and the cellular mechanism underlying burst and pause production in dopamine neurons has not been fully characterized. This is largely due to the difficulty in accurately duplicating bursts and pauses under controlled experimental conditions such as those attainable during in vitro experiments. Recently, we have determined a simple procedure to induce bursts and pauses in vitro that resemble those observed in vivo in every detail. This technical breakthrough allows for direct tests of the predictions of a mathematical model and a detailed cellular mechanism of bursting can be obtained. Computer simulations suggest NMDA receptors uniquely act to amplify the influence that the intrinsic frequencies of calcium- dependent oscillations within the dendrites have on the slower oscillations within the soma to initiate burst production. We have also recently shown that pauses in DA neurons may be generated by a mechanism completely different from that responsible for bursts. The specific aims in this proposal are designed to investigate the dopamine neuron pause and bursting mechanism and determine the effects of GABAergic receptors and of two phosphoinositide (Pl)- coupled receptors: the metabotropic glutamate receptor (mGluR) and the a-adrenoceptor. All these receptors can have differential effects on DA neuron firing pattern depending on the timing and duration of receptor activation. The experiments in this proposal implement both electrophysiological and confocal imaging techniques, along with computational modeling, to determine the cellular mechanisms of the reward prediction error. [unreadable] [unreadable] [unreadable]